Hayar, Abdallah and Patrice G. Guyenet. Prototypical imidazoline-1 receptor ligand moxonidine activates alpha2-adrenoceptors in bulbospinal neurons of the RVL. J. Neurophysiol. 83: 766 -776, 2000. Moxonidine is an antihypertensive drug that lowers sympathetic vasomotor tone by stimulating either alpha2-adrenergic (␣2-AR) or imidazoline I1 receptors within the rostral ventrolateral medulla (RVL). In this study, we investigated the effects of moxonidine (10 M) on RVL neurons in brain stem slices of neonatal rats. We recorded mainly from retrogradely labeled RVL bulbospinal neurons (putative presympathetic neurons) except for some extracellular recordings. Prazosin was used to block alpha1-adrenoceptors. Moxonidine inhibited the extracellularly recorded discharges of all spontaneously active RVL neurons tested (bulbospinal and unidentified). This effect was reversed or blocked by the selective ␣2-AR antagonist SKF 86466 (10 M). In contrast, the I1 imidazoline ligand AGN 192403 (10 M) had no effect on the spontaneous activity. In whole cell recordings (holding potential Ϫ70 mV), moxonidine produced a small and variable outward current (mean 7 pA). This current was observed in both tyrosine hydroxylase-immunoreactive and other bulbospinal neurons and was blocked by SKF 86466. Excitatory postsynaptic currents (EPSCs) evoked by focal electrical stimulation were isolated by incubation with gabazine and strychnine, and inhibitory postsynaptic currents (IPSCs) were isolated with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Moxonidine reduced the amplitude of the evoked EPSCs (EC 50 ϭ 1 M; 53% inhibition at 10 M) but not their decay time constant (5.6 ms). The effect of moxonidine on EPSCs persisted in barium (300 M) and was reduced ϳ80% by SKF 86466. Moxonidine also reduced the amplitude of evoked IPSCs by 63%. In conclusion, moxonidine inhibits putative RVL presympathetic neurons both presynaptically and postsynaptically. All observed effects in the present study are consistent with an ␣2-AR agonist activity of moxonidine.
I N T R O D U C T I O NCentrally acting antihypertensive drugs with an imidazoline structure, like clonidine and moxonidine, are effective in treating moderate to severe forms of hypertension (Armah et al. 1988;Prichard et al. 1997;Schafer et al. 1995;Ziegler et al. 1996). There is general agreement that a major site of action of these drugs is within the rostral ventrolateral medulla (RVL) (Punnen et al. 1987; reviewed by Reis 1996), but their specific neuronal targets are unknown. The RVL is critical for sympathetic tone generation and blood pressure control because it contains bulbospinal neurons (presympathetic neurons) that contribute the major excitatory drive to sympathetic vasoconstrictor and cardiac preganglionic neurons (McAllen et al. 1997;Sun 1995). The presympathetic neurons include a catecholaminergic cell group (C1 cells) that express the A subtype of ␣2-ARs (Guyenet et al. 1994). Activation of ␣2-ARs by norepinephrine (NE) in RVL bulbospinal neurons in vitro (C1 cells and others) acti...